1. Field of the Invention
The present invention is directed to the field of pharmacology. In one aspect, the invention is directed to improved salts of guanylhydrazone compounds. In another aspect, the invention is directed to the formulation of pharmaceutical compositions containing improved salts of guanylhydrazone compounds. The guanylhydrazone salts may be used for preventive or therapeutic regimens or for the identification of candidate compounds for producing effective drugs having increased or modulated solubility in water or a neutral solution for enhancing or modulating bioavailability.
2. Related Art
United States Patent Application Publication No. 2004/0043079 to D'Souza relates to microencapsulation as a delivery vehicle for a drug. The guanylhydrazone compound Semapimod is disclosed in one embodiment.
United States Patent Application Publication No. 2003/0134904 to Giordano et al. relates to guanylhydrazone compounds for inhibiting RNase P activity.
United States Patent Application Publication No. 2003/0203969 to Bevec et al. relates to pharmaceutically active aromatic guanylhydrazone compounds.
United States Patent Application Publication No. 2002/0028851 to Bianchi et al. relates to guanylhydrazone compounds and their uses to treat inflammatory conditions.
U.S. Pat. Nos. 6,673,777 and 6,143,728 to Tracey et al. relate to guanylhydrazone compounds and their uses for treating diseases associated with T cell activation.
U.S. Pat. Nos. 6,248,787; 6,180,676; 6,022,900; 6,008,255; 5,859,062; 5,854,289; 5,849,794; 5,753,684; 5,750,573; and 5,599,984 all to Bianchi et al. relate to guanylhydrazone compounds and their uses to treat inflammatory conditions.
All references cited herein are incorporated by reference for all purposes.
3. Background of the Technology
Solubility in solution, either for a drug compound with a recognized activity or for a drug candidate compound, is almost always required before the compound can be analyzed or significant bioavailability achieved. Solubility in water or some aqueous or neutral solution is desirable as high solubility eases molecular pharmacology screening as well as biodistribution.
In vitro studies involving such aspects as receptor binding, enzyme inhibition, and cell cultures and studies with isolated organs are all facilitated when the compound is made soluble in H2O or other neutral media. When testing highly water insoluble material for in vitro assays, the common procedure to attain water solubility is to prepare a solution using an organic solvent (DMSO, polyethylene glycol, EtOH, etc.) and then proceed to various aqueous dilutions. In following this regimen, there is always the possibility that the compound will precipitate out during a dilution. Furthermore, any precipitation may not be properly considered if it is not noticeable or the precipitate easily adheres to the wall of the testing vessel.
Most organic acids or bases are only poorly soluble in water, whereas many corresponding salts render the drug substance ionized in H2O and hence made water soluble. Salts that are soluble in water are also ideally suited for the preparation of injectable sterile aqueous solutions. Also, fast dissolution of the active principle contained in solid dosage forms, such as for quick release tablets or hard-gelatine capsules will rely on the aqueous solubility of the drug.
When considering in vivo testing, solubility in H2O facilitates all studies in which parenteral administration is required. In pharmacokinetics, a reliable determination of absolute bioavailability via oral administration is needed before a comparison is possible with an amount administered intravenously because a dose entering the system by the parenteral route is a precisely known reference. Aqueous solubility is particularly important in toxicity studies wherein the digestibility of a compound in an animal will leave uncertainty as to whether an insoluble compound is either toxic or just incompletely absorbed.
On a therapeutic level, the major concern for finding a water-soluble drug resides in the possibility this solubility provides for intravenous administration. The water solubility of a drug is particularly important in drugs for emergency treatments that will permit therapeutic plasma levels to be reached in a very short period of time. Intravenous administration is often the only access available when a patient is otherwise incapacitated in an operation or some emergency situation. Also, water solubility is needed for several types of pharmaceutical dosage formats. Apart from parenteral injection or infusion, water solubility is important for producing aqueous drops for ocular or nasal administration, or aqueous syrup for oral administration.
For oral consumption of a drug compound, the significance of water solubility to pharmacokinetics cannot be underestimated. This is particularly so when the absorption step for the compound is preceded by a dissolution step of the orally ingested dosage format. The in-vivo dissolution step is often the rate determining step for drug absorption. Also, highly water-soluble drugs are, by the fact itself, less toxic than lower water-soluble drugs due to their facilitated renal clearance. They will have a lesser tendency to accumulate in an organism thus avoiding overload to the liver.
Complex guanylhydrazones have been reported in the patent literature above. For instance, U.S. Pat. No. 5,599,984 to Bianchi et al. listed above discloses hydrochloride salts of complex guanylhydrazone compounds with some degree of water solubility. However, the high acidity associated with some hydrochloride salts, upon dissociation, can cause cellular damage and is a recognized source of phlebitis. Stranz et al., Int. J. Pharm. Compounding (2002), v. 6, n. 3, pp. 216-220. Thus, there is a need in the art to develop salts of guanylhydrazone compounds, and in particular salts of complex guanylhydrazone compounds, having both high water solubility and lower probability of cellular insult due to the acidity of the salt upon dissociation in solution.